Researchers Identify How Aggressive Breast Cancer Suppresses Immune System

Researchers identified how aggressive breast cancer suppresses the immune system in studies published this month. According to the research, tumor-associated macrophages and myeloid-derived suppressor cells inhibit T cell activation and alter bone marrow function to promote tumor growth and immune evasion.

Tumor-associated macrophages (TAMs) suppress cytotoxic T lymphocyte activation by limiting antigen presentation in breast cancer, according to a study published this month in the Journal of Immunology. The study, led by researchers at the University of California, San Francisco, found that TAMs release anti-inflammatory cytokines that recruit regulatory T cells (Tregs), which further inhibit effector T cell activation.

In the MMTV-PyMT mouse model of breast cancer, TAMs exhibited elevated cathepsin protease activity driven by interleukin-4 (IL-4) from tumor and T cells, promoting tumor invasion and angiogenesis.

Breast cancer tumors disrupt bone marrow function by altering the local environment to suppress anti-tumor immune responses, researchers at the University of Texas MD Anderson Cancer Center reported in Cancer Research on June 5. The team demonstrated that osteoprogenitor cells communicate with granulocyte-monocyte progenitors (GMPs) through matrix metalloproteinase-13 (MMP-13), leading GMPs to produce neutrophils and monocytes that accumulate in tumors and promote growth by suppressing immunity. These changes persisted even after tumor removal in animal models. Inhibiting MMP-13 accelerated immune recovery and restored the efficacy of immunotherapy in preclinical trials.

Myeloid-derived suppressor cells (MDSCs) in the breast cancer tumor microenvironment secrete interleukin-6 (IL-6), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-β), impairing immune cell function, according to findings published on June 10 in Frontiers in Immunology by researchers at the Dana-Farber Cancer Institute. The study detailed that chemokines CCL2 and CXCL12, produced by fibroblasts and tumor cells, recruit monocytes that differentiate into immunosuppressive TAMs. These TAMs release interleukin-1β (IL-1β), which attracts neutrophils, immature dendritic cells, and Tregs, contributing to adaptive immune suppression in breast cancer.

Natural killer (NK) cell function is impaired in early-stage HER2-positive breast cancer due to co-expression of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on CD16CD56dim NK cells, according to a study from Memorial Sloan Kettering Cancer Center published June 12 in Nature Communications. Interferon-gamma (IFN-γ) was shown to increase PD-L1 expression, amplifying PD-1–mediated suppression in the tumor microenvironment. PD-1 blockade in humanized CB-BRGS triple-negative breast cancer (TNBC) mouse models restored NK cell function and promoted tumor regression. The study also identified oncogenic pathways that suppress NKG2D ligands MICA and MICB, impairing NK cell recognition.

Breast cancer cells expressing chemokine receptor CCR2 inhibit dendritic cell infiltration and maturation, according to research published June 15 in Cancer Immunology Research by investigators at the University of Chicago. The study showed that CCR2 on tumor cells disrupts the maturation of cross-presenting dendritic cells, which are critical for T-cell activation. Mouse models with CCR2-positive tumors exhibited significantly fewer dendritic cells compared to controls. Blocking CCR2 improved drug penetration and immune response, with CCR2 inhibitors having been tested clinically since 2012.

Tumor-associated macrophages secrete chemokines CCL22 and CCL20 that recruit regulatory T cells, creating an immunosuppressive microenvironment, according to a study published June 8 in OncoImmunology by researchers at Johns Hopkins University. Cancer-associated fibroblasts (CAFs) secrete elevated prostaglandin E2 (PGE2) in response to NK cells; activation of EP2 and EP4 receptors by PGE2 inhibited IFN-γ production by 66 to 86 percent. IL-10 produced by Tregs, TAMs, and B cells was found to suppress IFN-γ and tumor necrosis factor-alpha (TNF-α) production and reduce antigen-presenting cell function.

Targeting TAMs with anti-colony stimulating factor-1 receptor (CSF-1R) antibodies depletes macrophages and converts their phenotype, enhancing anti-PD-1 immunotherapy efficacy in preclinical breast cancer models, according to data published June 3 in Clinical Cancer Research by a team at the National Cancer Institute. The study highlighted that TAM depletion overcomes immune suppression and promotes durable anti-tumor immunity. Similarly, CCR2 blockade on tumor cells improved immune responses beyond its known role in immune cell recruitment, as reported by the University of Chicago group.

Inhibiting MMP-13 in bone marrow disruption models restored immunotherapy effectiveness, according to MD Anderson researchers. Their June 5 publication indicated that eliminating MMP-13 reversed the tumor-induced bone marrow changes that suppress immune recovery. Additionally, specific macrophage inhibition restored anti-tumor immune responses in mouse models, as demonstrated in a study from the University of California, San Francisco, published June 9.

The interplay of cytokine and chemokine networks in breast cancer promotes tumor progression and immune evasion. TAMs upregulate mesenchymal markers such as vimentin and transcription factors Twist, Snail, and Slug in cancer cells, enhancing mesenchymal stemness, according to research from Johns Hopkins University published June 8. IL-1β from TAMs expanded pro-metastatic neutrophils, further contributing to tumor dissemination. In non-invasive breast cancers, CCL2-recruited CD206+/Tie2+ macrophages downregulated E-cadherin, facilitating tumor cell dissemination, as reported in the same study.

These findings build on a growing body of research illustrating the complex mechanisms breast cancer employs to evade immune surveillance. The studies, conducted at multiple U.S. institutions and published between June 1 and June 15, provide detailed molecular targets for future therapies. Clinical trials targeting CCR2 and CSF-1R have been ongoing since 2012, while new approaches focusing on MMP-13 and TAM modulation are advancing in preclinical stages.